Harnessing oral mucosa vaccination to drive protective HIV antibody responses

开发有效的艾滋病毒/艾滋病疫苗仍然是一个重要的全球卫生目标，以抑制和 扭转目前世界范围内艾滋病毒-1的高水平传播。到目前为止，已经有四个 在这些只有RV144的大型艾滋病毒-1疫苗试验中，显示出对艾滋病毒的有限但显著的保护(31.2%)。 1个收购。对这项研究结果的评估揭示了一些关键的相关因素 保护，包括针对环境病毒V1V2区构象表位的抗体。很明显， 需要新的疫苗接种方法来改善在RV144试验中的发现，通过产生高 V1-V2和功能性抗体的滴度，创造长寿的B细胞记忆，并推动抗体成熟 朝着广泛的中和活动迈进。口腔粘膜组织提供了一个独特的环境，在其中 接种疫苗，由于其可接近的淋巴器官，高密度的免疫细胞和增加的潜力 产生能够防止在粘膜表面感染HIV-1的粘膜反应。我们提出了一个 将重组HIV-1三聚体包膜蛋白疫苗直接经口接种的接种策略 黏膜(颊粘膜)通过上皮内(IEP)接种。疫苗将用两种疫苗进行测试 佐剂配方旨在通过TLR4和TLR7/8途径刺激强大的先天诱导。这个 这项建议的目标是优化HIV-1包膜蛋白的口腔黏膜疫苗接种，以增强HIV-1包膜蛋白的免疫效果。 特异性抗体反应，并通过进行一次 疫苗诱导免疫的彻底多参数评估。第一个具体目标是评估 对疫苗的先天免疫反应，重点是疫苗对口腔粘膜的影响 疫苗是通过IEP注射来注射的。先天免疫变化很有趣，因为它们有可能 揭示了一种生物分子特征，我们相信这将对应于优越的HIV-1ENV抗体反应。 第二个和第三个特定目标将评估向口腔粘膜供应Env是否会推动优势 粘膜部位和全身的抗体反应。中和活性和ADCVI活性的评估 将提供与先天免疫研究结果相关联的功能评估 回应。目标2和目标3还将涉及通过以下方式对抗环境病毒抗体反应的机械性评估 对这些猕猴的CD4T滤泡辅助细胞反应和抗体成熟度的评估。在……里面 除了口腔黏膜IEP疫苗接种的优化和详尽的多参数分析外， 索多拉和萨瑟实验室的综合专业知识是这项应用的主要优势之一。这个 本提案中概述的实验利用口服黏膜IEP递送下一代HIV-1环境蛋白 抗原，以及对先天和获得性免疫反应的评估。这一全面的 方法带来了高度的信心，即进行这些研究将使 为艾滋病毒-1疫苗开发作出贡献，并推动扭转目前的艾滋病毒-1大流行的努力。

Developing an effective vaccine against HIV/AIDS remains an important global health target to inhibit and reverse the high level of HIV-1 transmission currently ongoing around the world. To date, there have been four large HIV-1 vaccine trials, of these only RV144 exhibited a limited, but significant protection (31.2%) from HIV- 1 acquisition. The assessment of the results from this study has revealed a number of key correlates of protection, including antibodies that target a conformational epitope in the V1V2 region of Env. It is clear that new vaccination methodologies are needed to improve upon the findings in the RV144 trial by generating high titers of V1-V2 and functional antibodies, creating long lived B cell memory, and driving antibody maturation toward broadly neutralizing activity. The oral mucosal tissues provide a unique environment in which to vaccinate, owing to its accessible lymphoid organs, high density of immune cells and increased potential for generating a mucosal response that is able to prevent HIV-1 acquisition at a mucosal surface. We propose a vaccination strategy to deliver recombinant HIV-1 trimeric Envelope (Env) protein vaccines directly to the oral mucosa (buccal mucosa of the cheek) by intra-epithelial (IEp) vaccination. Vaccines will be tested with two adjuvant formulations designed to stimulate strong innate induction through TLR4 and TLR7/8 pathways. The goal of this proposal is to optimize oral mucosal vaccination of the HIV-1 Env protein in order to enhance Env- specific antibody responses, and to characterize the effect of oral vaccination with Env by conducting a thorough multi-parametric assessment of vaccine-elicited immunity. The first Specific Aim will assess the innate immune response to the vaccine, with a focus on the influence of the vaccine at the buccal mucosa where the vaccine is administered by IEp injection. Innate immune changes are interesting for their potential to reveal a biomolecular signature that we believe will correspond to superior HIV-1 ENV antibody responses. The second and third Specific Aims will evaluate whether supplying Env to the oral mucosa drives superior antibody responses at mucosal sites and systemically. An assessment of the neutralization and ADCVI activity will provide a functional assessment that can be correlated with the findings from studies of the innate immune response. Aims 2 and 3 will also involve a mechanistic assessment of the anti-Env antibody response through an assessment of both CD4 T Follicular Helper cell responses and antibody maturation in these macaques. In addition to the optimization of oral mucosal IEp vaccination and the exhaustive multi-parametric analyses, the combined expertise of the Sodora and Sather laboratories is one of the major strengths of this application. The experiments outlined in this proposal utilize an oral mucosal IEp delivery of next-generation HIV-1 Env antigens, as well as an assessment of both innate and adaptive immune responses. This comprehensive approach results in a high degree of confidence that undertaking these studies will make a significant contribution to HIV-1 vaccine development and advance efforts toward reversing the ongoing HIV-1 pandemic.